Nasopharyngeal lymphatic plexus is a hub for cerebrospinal fluid drainage.

Cerebrospinal fluid (CSF) in the subarachnoid space around the brain has long been known to drain through the lymphatics to cervical lymph nodes1-17, but the connections and regulation have been challenging to identify. Here, using fluorescent CSF tracers in Prox1-GFP lymphatic reporter mice18, we found that the nasopharyngeal lymphatic plexus is a major hub for CSF outflow to deep cervical lymph nodes. This plexus had unusual valves and short lymphangions but no smooth-muscle coverage, whereas downstream deep cervical lymphatics had typical semilunar valves, long lymphangions and smooth muscle coverage that transported CSF to the deep cervical lymph nodes. α-Adrenergic and nitric oxide signalling in the smooth muscle cells regulated CSF drainage through the transport properties of deep cervical lymphatics. During ageing, the nasopharyngeal lymphatic plexus atrophied, but deep cervical lymphatics were not similarly altered, and CSF outflow could still be increased by adrenergic or nitric oxide signalling. Single-cell analysis of gene expression in lymphatic endothelial cells of the nasopharyngeal plexus of aged mice revealed increased type I interferon signalling and other inflammatory cytokines. The importance of evidence for the nasopharyngeal lymphatic plexus functioning as a CSF outflow hub is highlighted by its regression during ageing. Yet, the ageing-resistant pharmacological activation of deep cervical lymphatic transport towards lymph nodes can still increase CSF outflow, offering an approach for augmenting CSF clearance in age-related neurological conditions in which greater efflux would be beneficial.

Characterization of Codeine Treatment Responders Among Patients with Refractory or Unexplained Chronic Cough: A Prospective Real-World Cohort Study.

PURPOSE: Codeine is a narcotic antitussive often considered for managing patients with refractory or unexplained chronic cough. This study aimed to evaluate the proportion and characteristics of patients who responded to codeine treatment in real-world practice. METHODS: Data from the Korean Chronic Cough Registry, a multicenter prospective cohort study, were analyzed. Physicians assessed the response to codeine based on the timing and degree of improvement after treatment initiation. Follow-up assessments included the Leicester Cough Questionnaire and cough severity visual analog scale at six months. In a subset of subjects, objective cough frequency was evaluated following the initiation of codeine treatment. RESULTS: Of 305 patients, 124 (40.7%) responded to treatments based on anatomic diagnostic protocols, while 181 (59.3%) remained unexplained or refractory to etiological treatments. Fifty-one subjects (16.7%) were classified as codeine treatment responders (those showing a rapid and clear response), 57 (18.7%) as partial responders, and 62 (20.3%) as non-responders. Codeine responders showed rapid improvement in objective cough frequency and severity scores within a week of the treatment. At 6 months, responders showed significantly improved scores in cough scores, compared to non-responders. Several baseline parameters were associated with a more favorable treatment response, including older age, non-productive cough, and the absence of heartburn. CONCLUSIONS: Approximately 60% of chronic cough patients in specialist clinics may require antitussive drugs. While codeine benefits some, only a limited proportion (about 20%) of patients may experience rapid and significant improvement. This underscores the urgent need for new antitussive drugs to address these unmet clinical needs.

Ultrafast fluorescence depolarisation in green fluorescence protein tandem dimers as hydrophobic environment sensitive probes.

Advances in ultra-fast photonics have enabled monitoring of biochemical interactions on a sub nano-second time scale. In addition, picosecond dynamics of intermolecular energy transfer in fluorescent proteins has been observed. Here, we present the development of a genetically encoded fluorescent sensor that can detect changes in hydrophobicity by monitoring ultrafast fluorescence depolarisation. Our sensor is composed of a pair of dimeric enhanced green fluorescent proteins (dEGFPs) linked by a flexible amino-acid linker. We show dimerisation is perturbed by the addition of glycerol which interferes with the hydrophobic interaction of the two proteins. Time-resolved fluorescence anisotropy revealed a systematic attenuation of ultrafast fluorescence depolarisation when the sensor was exposed to increasing glycerol concentrations. This suggests that as hydrophobicity increases, dEGFP pairing decreases within a tandem dimer. Un-pairing of the protein fluorophores dramatically alters the rate of energy transfer between the proteins, resulting in an increase in the limiting anisotropy of the sensor.

Automotive 2.1 µm Full-Depth Deep Trench Isolation CMOS Image Sensor with a 120 dB Single-Exposure Dynamic Range.

An automotive 2.1 µm CMOS image sensor has been developed with a full-depth deep trench isolation and an advanced readout circuit technology. To achieve a high dynamic range, we employ a sub-pixel structure featuring a high conversion gain of a large photodiode and a lateral overflow of a small photodiode connected to an in-pixel storage capacitor. With the sensitivity ratio of 10, the expanded dynamic range could reach 120 dB at 85 °C by realizing a low random noise of 0.83 e- and a high overflow capacity of 210 ke-. An over 25 dB signal-to-noise ratio is achieved during HDR image synthesis by increasing the full-well capacity of the small photodiode up to 10,000 e- and suppressing the floating diffusion leakage current at 105 °C.

Toll-like receptor mediated inflammation requires FASN-dependent MYD88 palmitoylation.

Toll-like receptor (TLR)/myeloid differentiation primary response protein (MYD88) signaling aggravates sepsis by impairing neutrophil migration to infection sites. However, the role of intracellular fatty acids in TLR/MYD88 signaling is unclear. Here, inhibition of fatty acid synthase by C75 improved neutrophil chemotaxis and increased the survival of mice with sepsis in cecal ligation puncture and lipopolysaccharide-induced septic shock models. C75 specifically blocked TLR/MYD88 signaling in neutrophils. Treatment with GSK2194069 that targets a different domain of fatty acid synthase, did not block TLR signaling or MYD88 palmitoylation. De novo fatty acid synthesis and CD36-mediated exogenous fatty acid incorporation contributed to MYD88 palmitoylation. The binding of IRAK4 to the MYD88 intermediate domain and downstream signal activation required MYD88 palmitoylation at cysteine 113. MYD88 was palmitoylated by ZDHHC6, and ZDHHC6 knockdown decreased MYD88 palmitoylation and TLR/MYD88 activation upon lipopolysaccharide stimulus. Thus, intracellular saturated fatty acid-dependent palmitoylation of MYD88 by ZDHHC6 is a therapeutic target of sepsis.

Synthesis of 2D semiconducting single crystalline Bi2S3 for high performance electronics.

2-Dimensional (2D) semiconducting materials are attractive candidates for future electronic device applications due to the tunable bandgap, transparency, flexibility, and downscaling to the atomic level in material size and thickness. However, 2D materials have critical issues regarding van der Waals contact, interface instability and power consumption. In particular, the development of semiconducting electronics based on 2D materials is significantly hindered by a low charge-carrier mobility. In order to improve the critical shortcoming, diverse efforts have been made in synthesis and device engineering. Here, we propose a synthesis method of single crystalline 2D Bi2S3 by chemical vapor deposition for high performance electronic device applications. The ion-gel gated field effect transistor with the as-grown Bi2S3 on the SiO2 substrate exhibits a high mobility of 100.4 cm2 V-1 S-1 and an on-off current ratio of 104 under a low gate voltage below 4 V at room temperature without chemical doping and surface engineering. The superior performance is attributed to the high crystal quality of Bi2S3 that shows low sulfur vacancies and atomic ratio close to the ideal value (2 : 3) under a rich sulfur growth process using H2S gas instead of sulfur powder. The synthesis method will provide a platform to realize high performance electronics and optoelectronics based on 2D semiconductors.

Functionalization of a Single C-F Bond of Trifluoromethylarenes Assisted by an ortho-Silyl Group Using a Trityl-Based All-in-One Reagent with Ytterbium Triflate Catalyst.

Catalytic thiolation and azidation of a single C-F bond of trifluoromethylarenes were achieved assisted by an ortho-silyl group with all-in-one reagents to generate a trityl cation and nucleophiles. The reactions catalyzed by ytterbium triflate efficiently afforded a wide variety of difluoromethylenes avoiding the further C-F bond cleavage, by virtue of the mild conditions without the generation of a Brønsted acid.

VenusA206 Dimers Behave Coherently at Room Temperature.

Fluorescent proteins (FPs) have revolutionized cell biology by allowing genetic tagging of specific proteins inside living cells. In conjunction with Förster's resonance energy transfer (FRET) measurements, FP-tagged proteins can be used to study protein-protein interactions and estimate distances between tagged proteins. FRET is mediated by weak Coulombic dipole-dipole coupling of donor and acceptor fluorophores that behave independently, with energy hopping discretely and incoherently between fluorophores. Stronger dipole-dipole coupling can mediate excitonic coupling in which excitation energy is distributed near instantaneously between coherently interacting excited states that behave as a single quantum entity. The interpretation of FP energy transfer measurements to estimate separation often assumes that donors and acceptors are very weakly coupled and therefore use a FRET mechanism. This assumption is considered reasonable as close fluorophore proximity, typically associated with strong excitonic coupling, is limited by the FP ß-barrel structure. Furthermore, physiological temperatures promote rapid vibrational dephasing associated with a rapid decoherence of fluorophore-excited states. Recently, FP dephasing times that are 50 times slower than traditional organic fluorophores have been measured, raising the possibility that evolution has shaped FPs to allow stronger than expected coupling under physiological conditions. In this study, we test if excitonic coupling between FPs is possible at physiological temperatures. FRET and excitonic coupling can be distinguished by monitoring spectral changes associated with fluorophore dimerization. The weak coupling mediating FRET should not cause a change in fluorophore absorption, whereas strong excitonic coupling causes Davydov splitting. Circular dichroism spectroscopy revealed Davydov splitting when the yellow FP VenusA206 dimerizes, and a novel approach combining photon antibunching and fluorescence correlation spectroscopy was used to confirm that the two fluorophores in a VenusA206 homodimer behave as a single-photon emitter. We conclude that excitonic coupling between VenusA206 fluorophores is possible at physiological temperatures.

Ultrahigh Photoresponsive Device Based on ReS2 /Graphene Heterostructure.

Heterostructures that combine graphene and transition metal dichalcogenides, such as MoS2 , MoTe2 , and WS2 , have attracted attention due to their high performances in optoelectronic devices compared to homogeneous systems. Here, a photodevice based on a hybrid van der Waals heterostructure of rhenium disulfide (ReS2 ) and graphene is fabricated using the stacking method. The device presents a remarkable ultrahigh photoresponsivity of 7 × 105 A W-1 and a detectivity of 1.9 × 1013 Jones, along with a fast response time of less than 30 ms. Tremendous photocurrents are generated in the heterostructure due to the direct bandgap, high quantum efficiency, and strong light absorption by the multilayer ReS2 and the high carrier mobility of graphene. The ReS2 /graphene heterostructured device displays a high photocurrent under the applied gate voltages due to the photogating effect induced by the junction between graphene and ReS2 . The ReS2 /graphene heterostructure may find promising applications in future optoelectronic devices, providing a high sensitivity, flexibility, and transparency.

Semi-random multicore fibre design for adaptive multiphoton endoscopy.

This paper reports the development, modelling and application of a semi-random multicore fibre (MCF) design for adaptive multiphoton endoscopy. The MCF was constructed from 55 sub-units, each comprising 7 single mode cores, in a hexagonally close-packed lattice where each sub-unit had a random angular orientation. The resulting fibre had 385 single mode cores and was double-clad for proximal detection of multiphoton excited fluorescence. The random orientation of each sub-unit in the fibre reduces the symmetry of the positions of the cores in the MCF, reducing the intensity of higher diffracted orders away from the central focal spot formed at the distal tip of the fibre and increasing the maximum size of object that can be imaged. The performance of the MCF was demonstrated by imaging fluorescently labelled beads with both distal and proximal fluorescence detection and pollen grains with distal fluorescence detection. We estimate that the number of independent resolution elements in the final image - measured as the half-maximum area of the two-photon point spread function divided by the area imaged - to be ~3200.

Increased epicardial adipose tissue thickness is a predictor of new-onset diabetes mellitus in patients with coronary artery disease treated with high-intensity statins.

BACKGROUND: Statins are widely used for lipid lowering in patients with coronary artery disease (CAD), but increasing evidence indicates an association between statin use and new-onset of diabetes mellitus (NODM). Epicardial adipose tissue (EAT) refers to the visceral fat surrounding the heart, which is associated with metabolic diseases. We sought to determine the association between EAT thickness and NODM in CAD patients treated with high-intensity statins. METHODS: We conducted a retrospective medical record review of CAD patients treated with high-intensity statins for at least 6 months after percutaneous coronary intervention performed between January 2009 and June 2013 at Seoul National University Bundang Hospital. EAT thickness was measured by echocardiography using standardized methods. RESULTS: A total of 321 patients were enrolled, who received high-intensity statins for a mean of 952 days; atorvastatin 40 mg in 204 patients (63.6%), atorvastatin 80 mg in 57 patients (17.8%), and rosuvastatin 20 mg in 60 patients (18.7%). During the follow-up period of 3.9 ± 1.7 years, NODM occurred in 40 patients (12.5%). On Cox proportional-hazard regression analysis, EAT thickness at systole [for each 1 mm: hazard ratio (HR) 1.580; 95% confidence interval (CI) 1.346-1.854; P < 0.001] and prediabetes at baseline (HR 4.321; 95% CI 1.998-9.349; P < 0.001) were the only independent predictors of NODM. Using binary cutoff values derived from the receiver operating characteristic curve analysis, EAT thickness at systole larger than 5.0 mm had an HR of 3.402 (95% CI 1.751-6.611, P < 0.001), sensitivity of 52.5%, and specificity of 80.8% for predicting NODM. Also, patients with EAT thickness ≥ 5 mm and prediabetes at baseline had a 12.0-times higher risk of developing NODM compared to the risk noted in patients with EAT thickness < 5 mm and normal glucose tolerance at baseline. CONCLUSION: Epicardial adipose tissue thickness at systole is a consistent independent predictor of NODM in patients with CAD treated with high-intensity statins. Such predictors may help physicians plan adequate surveillance for early detection of NODM.

Age-related prevalence of chronic rhinosinusitis and nasal polyps and their relationships with asthma onset.

BACKGROUND: Chronic rhinosinusitis (CRS) is a major disease condition with high morbidity and can influence lower airway disease status in adults. However, its associations with adult asthma onset and activity have not been examined in detail in a general adult population. OBJECTIVE: To investigate relationships between CRS with nasal polyps (CRSwNP) and asthma characteristics. METHODS: A cross-sectional data set of 17,506 adult participants (≥18 years old) in the Korean National Health and Nutrition Examination Survey from 2010 through 2012 was analyzed. CRS was defined using structured questionnaires according to the international guideline, and presence of nasal polyps was objectively assessed using nasal endoscopy. Presence of asthma and its onset and current activity were assessed using structured questionnaires. RESULTS: CRS was significantly related to asthma, but the relationships were distinct by CRS and asthma status. CRSwNP was significantly associated with adult-onset asthma (onset after 18 years of age) or late-onset asthma (onset after 40 years of age), whereas CRS without nasal polyps was related to childhood-onset asthma (onset before 18 years) or early-onset asthma (onset before 40 years) in adults. The 2 CRS subgroups showed significant associations with current asthma but not with past asthma. However, the comorbid asthma rate was lower than 10% among subjects with CRS. CONCLUSION: This study found distinct age-related patterns of CRSwNP and asthma and demonstrated their significant associations in a general population. However, the low prevalence of asthma in CRSwNP is in sharp contrast to findings in Western populations, which warrants further investigation for ethnic or regional differences in relationships between CRSwNP and asthma.

Predictive Role of Serum Cytokine Profiles in Acute Kidney Injury after Living Donor Liver Transplantation.

INTRODUCTION: Previous studies have shown that a higher serum interleukin- (IL-) 6 level is associated with a higher risk of acute kidney injury (AKI) development after major nontransplant surgery. Our study investigated the potential association of preoperative serum cytokine profiles with new AKI development in patients who underwent living donor liver transplantation (LDLT). METHODS: Serum levels of cytokines IL-2, IL-6, IL-10, IL-12, and IL-17, interferon-γ, and tumor necrosis factor- (TNF-) α were measured in 226 LDLT recipients preoperatively and analyzed retrospectively. Recipients with a preoperative functional impairment of the kidney were excluded. AKI was defined according to Kidney Disease: Improving Global Outcomes (KDIGO) criteria. RESULTS: In a univariate regression model, IL-6, IL-17, and TNF-α levels showed an association with AKI development after LDLT. Multivariate analysis showed an independent association of the preoperative serum IL-6 level with AKI development after LDLT and a significant relationship between higher serum IL-6 levels and a greater likelihood of developing AKI. Serum IL-6 levels were higher in patients with stage 3 AKI than in patients who did not develop AKI. CONCLUSIONS: Our results support the need for further investigations of IL-6 as a predictor of AKI development in patients undergoing LDLT.

Large-Area CVD-Grown Sub-2 V ReS2 Transistors and Logic Gates.

We demonstrated the fabrication of large-area ReS2 transistors and logic gates composed of a chemical vapor deposition (CVD)-grown multilayer ReS2 semiconductor channel and graphene electrodes. Single-layer graphene was used as the source/drain and coplanar gate electrodes. An ion gel with an ultrahigh capacitance effectively gated the ReS2 channel at a low voltage, below 2 V, through a coplanar gate. The contact resistance of the ion gel-gated ReS2 transistors with graphene electrodes decreased dramatically compared with the SiO2-devices prepared with Cr electrodes. The resulting transistors exhibited good device performances, including a maximum electron mobility of 0.9 cm2/(V s) and an on/off current ratio exceeding 104. NMOS logic devices, such as NOT, NAND, and NOR gates, were assembled using the resulting transistors as a proof of concept demonstration of the applicability of the devices to complex logic circuits. The large-area synthesis of ReS2 semiconductors and graphene electrodes and their applications in logic devices open up new opportunities for realizing future flexible electronics based on 2D nanomaterials.

An estimation framework for building information modeling (BIM)-based demolition waste by type.

Most existing studies on demolition waste (DW) quantification do not have an official standard to estimate the amount and type of DW. Therefore, there are limitations in the existing literature for estimating DW with a consistent classification system. Building information modeling (BIM) is a technology that can generate and manage all the information required during the life cycle of a building, from design to demolition. Nevertheless, there has been a lack of research regarding its application to the demolition stage of a building. For an effective waste management plan, the estimation of the type and volume of DW should begin from the building design stage. However, the lack of tools hinders an early estimation. This study proposes a BIM-based framework that estimates DW in the early design stages, to achieve an effective and streamlined planning, processing, and management. Specifically, the input of construction materials in the Korean construction classification system and those in the BIM library were matched. Based on this matching integration, the estimates of DW by type were calculated by applying the weight/unit volume factors and the rates of DW volume change. To verify the framework, its operation was demonstrated by means of an actual BIM modeling and by comparing its results with those available in the literature. This study is expected to contribute not only to the estimation of DW at the building level, but also to the automated estimation of DW at the district level.

Adaptive multiphoton endomicroscopy through a dynamically deformed multicore optical fiber using proximal detection.

This paper demonstrates multiphoton excited fluorescence imaging through a polarisation maintaining multicore fiber (PM-MCF) while the fiber is dynamically deformed using all-proximal detection. Single-shot proximal measurement of the relative optical path lengths of all the cores of the PM-MCF in double pass is achieved using a Mach-Zehnder interferometer read out by a scientific CMOS camera operating at 416 Hz. A non-linear least squares fitting procedure is then employed to determine the deformation-induced lateral shift of the excitation spot at the distal tip of the PM-MCF. An experimental validation of this approach is presented that compares the proximally measured deformation-induced lateral shift in focal spot position to an independent distally measured ground truth. The proximal measurement of deformation-induced shift in focal spot position is applied to correct for deformation-induced shifts in focal spot position during raster-scanning multiphoton excited fluorescence imaging.

Catalytic activity and thermal stability of horseradish peroxidase encapsulated in self-assembled organic nanotubes.

Horseradish peroxidase (HRP) was encapsulated in self-assembled lithocholic acid (LCA) based organic nanotubes and its catalytic activity before and after thermal treatment was measured for comparison with free HRP. The apparent kcat (kcat/Km) for nanotube encapsulated HRP remained almost the same before and after thermal treatment, reporting an average value of 3.7 ± 0.4 µM(-1) s(-1). The apparent kcat value for free HRP decreased from 14.8 ± 1.3 µM(-1) s(-1) for samples stored at 4 °C to 2.4 ± 0.1 µM(-1) s(-1) after thermal treatment for 8 h at 55 °C. The Michaelis-Menten constants, Km, determined for encapsulated HRP and free HRP were relatively unperturbed by storage conditions at 4 °C or thermally treated at 55 °C for varying time periods from 2-8 h, with encapsulated HRP having a slightly higher Km than free HRP (13.4 ± 0.9 µM versus 11.7 ± 0.4 µM). The amount of HRP encapsulated in LCA nanotubes increased dramatically when the mixture of HRP and LCA nanotubes was brought to an elevated temperature. Within 4 h of thermal treatment at 55 °C, the amount of HRP encapsulated by the LCA nanotubes was more than 4 times the amount of HRP encapsulated when equilibrated at 4 °C for 7 days. Molecular dynamics (MD) simulations show that the higher degree of exposure of hydrophobic residues in HRP at elevated temperatures enhances the hydrophobic interaction between HRP and the nanotube wall, resulting in the increased amount of HRP surface adsorption and, hence, the overall amount of encapsulation inside the nanotubes.

Borane-Catalyzed Reductive α-Silylation of Conjugated Esters and Amides Leaving Carbonyl Groups Intact.

Described herein is the development of the B(C6F5)3-catalyzed hydrosilylation of α,ß-unsaturated esters and amides to afford synthetically valuable α-silyl carbonyl products. The α-silylation occurs chemoselectively, thus leaving the labile carbonyl groups intact. The reaction features a broad scope of both acyclic and cyclic substrates, and the synthetic utility of the obtained α-silyl carbonyl products is also demonstrated. Mechanistic studies revealed two operative steps: fast 1,4-hydrosilylation of conjugated carbonyls and then slow silyl group migration of a silyl ether intermediate.

Single C-F Bond Cleavage of Trifluoromethylarenes with an ortho-Silyl Group.

The transformation of a single C-F bond of trifluoromethylarenes bearing a hydrosilyl group at the ortho position was achieved. The activation of the hydrosilyl group with a trityl cation in the presence of nucleophiles allowed for selective C-F bond functionalization, for example, by allylation, carboxylation, or chlorination. Further derivatization of the resulting fluorosilylarenes afforded various aromatic difluoromethylene compounds.